The goal of this proposal is to gain a better understanding of the inflammatory process induced by obesity in the liver and how it contributes to the pathogenesis of Non-Alcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus. While past studies have focused on events occurring within hepatocytes, very little has been learned about the role of other liver cells in this context and their relationship with hepatocytes during the onset of insulin resistance. Our previous studies have shown that one unrecognized component of this process is the accumulation in the liver of an infiltrating myeloid cell population. The recruitment of these cells appears to be dependent on the chemokine receptor CCR2, as mice deficient for this gene demonstrate impaired recruitment of macrophages after high fat feeding. Still unclear is the significance of this event for the dysregulation of glucose and lipid handling observed in the insulin resistant liver. The first aim of this proposal is to determine whether the recruitment and accumulation of hepatic IMCs is a common feature of fatty liver disease, and what signals may be directing this process. By determining the degree to which these cells are recruited in other models of steatosis such as alcoholic fatty liver disease and fasting induced steatosis, and correlating this with expression levels of chemokines in these states we will be able to make determinations as to the correlation of macrophage influx and chemokine expression. The second aim of this proposal is to demonstrate whether these infiltrating cells contribute to the inflammatory state and/or to the metabolic dysregulation of the steatotic liver. After altering chemotaxis of these cells by disruption of CCR2 liver specific insulin sensitivity and triglyceride accumulation will be assessed. To characterize this relationship in more detail, macrophages from obese livers will be isolated and cocultured with primary hepatocytes, and assayed for molecular, and biochemical indicators of glucose metabolism dysregulation. PUBLIC HEALTH RELEVANCE: Inflammation is known to play a role in the development of Type 2 Diabetes Mellitus, however very little is known about the critical cellular players in this process. By studying how immune cells in the liver promote inflammation and metabolic disease we will be able to better direct pharmacological interventions to prevent the progression of this disease.